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The antimicrobial peptides (AMPs) have been regarded as the next generation antibiotics. This study aimed to explore the AMP inhibitors of β-lactamase enzyme employing computational biology methods. Protein-peptide docking of Acinetobacter baumannii OXA-24 class D β-lactamase with AMPs (melittin and RP-1) were performed using HawkDock webserver. The docked complexes were subjected to energy property analysis through MM/GBSA, and binding affinity (ΔG (kcal/mol)) and stability (dissociation constant, KD (M)) prediction using PRODIGY. Both the AMPs, melittin and RP-1, were well docked with A. baumannii OXA-24. The top ranked OXA-24-melittin and OXA-24-RP-1 complexes were detected on the basis of the HawkDock scores (-2974.08 and -2825.83, respectively), thereafter by rescoring with MM/GBSA-based binding free energy (BFE) of -33.85 and -29.29 kcal/mol, respectively. The PRODIGY-based respective BFE (-8.0 and -10.0 kcal/mol) and KD (1.4 × 10-6 and 5 × 10-8 M) of the complexes revealed excellent protein-peptide binding affinity and complex stability. The iMODS-based molecular dynamic simulation authenticated the stability and molecular motion flexibility of the protein-peptide complexes. The quantum mechanics and molecular mechanics energy estimated using density-functional theory with CP2K software, for the electrostatic interaction of OXA-24-RP-1 (-218862.95 kcal/mol), was more favourable than the H-bonded interaction of OXA-24-melittin (-200620.21 kcal/mol), nevertheless both the peptides were found effective to inhibit OXA-24. Both the AMPs had toxicity profiles within the acceptable limits as predicted through pkCSM. Current findings indicate the potential supplement or replacement of conventionally used antibiotics with melittin and RP-1 to treating or averting A. baumannii infection by escaping the β-lactamases-mediated resistance.

The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) PG-O3B bond cleavage; 3) four concomitant events:W1-PO3 2 formation, OH2 and proton cleavage, nucleophilic attack by the OH2 against PG, and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes. [ABSTRACT FROM AUTHOR]

Recent discoveries of polar topological structures (e.g., skyrmions and merons) in ferroelectric/paraelectric heterostructures have opened a new field of polar topotronics. However, how complex interplay of photoexcitation, electric field and mechanical strain controls these topological structures remains elusive. To address this challenge, we have developed a computational approach at the nexus of machine learning and first-principles simulations. Our multiscale neural-network quantum molecular dynamics molecular mechanics approach achieves orders-of-magnitude faster computation, while maintaining quantum-mechanical accuracy for atoms within the region of interest. This approach has enabled us to investigate the dynamics of vortex states formed in PbTiO3 nanowires embedded in SrTiO3. We find topological switching of these vortex states to topologically trivial, uniformly polarized states using electric field and trivial domain-wall states using shear strain. These results, along with our earlier results on optical control of polar topology, suggest an exciting new avenue toward opto-electro-mechanical control of ultrafast, ultralow-power polar topotronic devices.

The MNPs @ [SiO2(OH)2]8 catalyzers were stablished via ab-initio and quantum mechanics & Molecular mechanic (QM/MM) simulation. The studies focus on how to improve the dispersion of composite particle for achieving high magnetic performances. The results revealed that the Fe3O4 @[SiO2 (OH)2]8(N2)8 as a cabalist exhibited better thermodynamic stability and dispersion than the magnetite nanoparticles. Furthermore, the particle size and magnetic properties of the [SiO2 (OH)2]8(N2)8 composite nanoparticles can be controlled by changing the functional groups. The electrical properties such as NMR Shielding, electron densities, energy densities, potential energy densities, ELF, LOL, of electron density, eta index, ECP, ESR and hyperfine interactions for Fe3O4@ [SiO2(OH)2]8(N2)8 have been calculated. As the catalyst could be easily recovered by magnetic separation and recycled for a few times without significant loss of its catalytic activity, we have calculated to obtain the stronger non bonded interaction in the Fe3O4@ [SiO2(OH)2]8(N2)8 system. This system can be used for antibiotics drug delivery instead of injection. The chemical shielding and several factors as the same electronegativity, magnetic anisotropy of π-systems will be changed due to the number of electrons The chemical shielding is a vector orientation function for all of the shielding parameters that can change in several places inside the shielding region.

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Raman spectroscopy is an effective tool to detect conformational changes and secondary structures of biological molecules. The amide-I band representing the amide carbonyl (C=O) stretching, with smaller contributions of C–N stretching and N–H bending is a signature band for protein secondary structure conformation. We have simulated the Raman spectra of insulin by a hybrid quantum-mechanics and molecular-mechanics (QM/MM) method with an aim to provide an accurate description of the amide-I band. To fulfil this aim we have considered three different QM/MM models with increasingly accurate description of the electrostatic environment for tyrosine (TYR), phenylalanine (PHE) and cystine (CYS) residues of insulin. All three models successfully describe the experimental Raman spectral features associated with the vibrational modes of the amino acid side chains. However, an accurate simulation of the amide-I band is achieved only in one of the three models, where the peptide backbone atoms together with its hydrogen bonding partners are treated with QM method. This work indicates that the accurate treatment of electrostatic interactions of the peptide backbone is crucial for correct simulation of the amide-I region, which acts as a spectral signature of proteins. [ABSTRACT FROM PUBLISHER]

The absorption mechanisms of collector and mineral surface structures play important roles in studies of lepidolite flotation. In this work, quantum mechanics (QM) and hybrid quantum mechanics/molecular mechanics (MM) methods were implemented to investigate the flotation mechanisms of lepidolite from muscovite, quartz and albite. The crystal structures, electron density distributions, bonds and the densities of states of lepidolite were calculated and compared with those of muscovite. The adsorption structures and energies of monomer dodecylammonium (DDA) on the three different minerals were also calculated. The headgroup of the DDA cation was found to adsorb on the surface of minerals, with its hydrophobic tail stretching into the vacuum slab, approximately perpendicular to the surface. Simulation results indicate that the purity of fine lepidolite is limited by the existence of muscovite, due to their similarities in surficial structure and properties. Other gangues were found to be removed efficiently with the use of acidic conditions. The results are in good agreement with other experiments. Compared with simple MM simulations, the use of the QM/MM methods to investigate the adsorption on minerals without specific forcefield parameters was concluded to be a more accurate method to attain monomer surfactant–mineral adsorption energies. [ABSTRACT FROM PUBLISHER]

Fracture is one of the most challenging ‘multi-scale’ problems to model: since crack propagation is driven by the concentration of a long-range stress field at an atomically sharp crack tip, an accurate description of the chemical processes occurring in the small crack tip region is therefore essential, as is the inclusion of a much larger region in the model systems. Both these requirements can be met by combining a quantum mechanical description of the crack tip with a classical atomistic model that captures the long-range elastic behaviour of the surrounding crystal matrix. Examples of the application of these techniques to fracture problems include: low-speed dynamical fracture instabilities in silicon; interactions between moving cracks and material defects such as dislocations or impurities; the crossover from thermally activated to catastrophic fracture; very slow crack propagation via kink formation and migration; and chemically activated fracture, where cracks advance under the concerted action of stress and corrosion by chemical species such as oxygen or water. [ABSTRACT FROM AUTHOR]

The major cytoskeleton protein actin undergoes cyclic transitions between the monomeric G-form and the filamentous F-form, which drive organelle transport and cell motility. This mechanical work is driven by the ATPase activity at the catalytic site in the F-form. For deeper understanding of the actin cellular functions, the reaction mechanism must be elucidated. Here, we show that a single actin molecule is trapped in the F-form by fragmin domain-1 binding and present their crystal structures in the ATP analog-, ADP-Pi-, and ADP-bound forms, at 1.15-Å resolutions. The G-to-F conformational transition shifts the side chains of Gln137 and His161, which relocate four water molecules including W1 (attacking water) and W2 (helping water) to facilitate the hydrolysis. By applying quantum mechanics/molecular mechanics calculations to the structures, we have revealed a consistent and comprehensive reaction path of ATP hydrolysis by the F-form actin. The reaction path consists of four steps: 1) W1 and W2 rotations; 2) P G -O 3B bond cleavage; 3) four concomitant events: W1-PO 3 - formation, OH - and proton cleavage, nucleophilic attack by the OH - against P G , and the abstracted proton transfer; and 4) proton relocation that stabilizes the ADP-Pi-bound F-form actin. The mechanism explains the slow rate of ATP hydrolysis by actin and the irreversibility of the hydrolysis reaction. While the catalytic strategy of actin ATP hydrolysis is essentially the same as those of motor proteins like myosin, the process after the hydrolysis is distinct and discussed in terms of Pi release, F-form destabilization, and global conformational changes.

Abstract: Channelrhodopsins (ChRs) are light-gated cation channels that mediate ion transport across membranes in microalgae (vectorial catalysis). ChRs gain increasing attention as useful tools for the analysis of neural networks in tissues and living animals (optogenetics). In fact, various mutagenesis approaches have realized practical applications with high reliability by enhancement of the expression level, channel kinetics control, and color tuning. Furthermore, the recently published x-ray structure has provided valuable information for further atomistic studies and engineering ChRs for a wider application. The present study is a computational attempt to describe the functional mechanism at the atomic level based on the x-ray structure. We present several structural characteristics that are highly involved in ion channel gating and ion transport, including (1) water distribution, (2) cation binding sites, (3) intrahelical hydrogen bond, (4) DC gate, and (5) active site. [Copyright &y& Elsevier]

The solvation and the solvatochromic behavior of the 5-(methylthio)-5′-nitro-2,2′-bithiophene 1 in diethyl ether, dichloromethane, acetonitrile, methanol and formamide was theoretically investigated with an iterative molecular and quantum mechanics (QM/MM) approach. Calculated longest-wavelength solvatochromic absorption band of 1, obtained as averages of statistically uncorrelated configurations, including the solute and explicit solvent molecules of the first and second solvation layer, were in excellent agreement with the experimental results. [Figure not available: see fulltext.] [ABSTRACT FROM AUTHOR]

The newly implemented quantum-chemical/molecular-mechanical (QM/MM) functionality of the Groningen molecular simulation (GROMOS) software for (bio)molecular simulation is described. The implementation scheme is based on direct coupling of the GROMOS C++ software to executables of the quantum-chemical program packages MNDO and TURBOMOLE, allowing for an independent further development of these packages. The new functions are validated for different test systems using program and model testing techniques. The effect of truncating the QM/MM electrostatic interactions at various QM/MM cutoff radii is discussed and the application of semiempirical versus density-functional Hamiltonians for a solute molecule in aqueous solution is compared. © 2012 Wiley Periodicals, Inc. [ABSTRACT FROM AUTHOR]

Abstract: The oligomerization of propene was investigated over H-MFI zeolites with varying Si/Al ratios. For a constant space time per active site, the conversion of propene as well as the selectivity to products of different carbon number was affected by the density of the sites within the zeolite. In particular, as the Si/Al ratio decreased, corresponding to an increase in site proximity, the rate of oligomerization per site decreased but the selectivity to dimers relative to cracking products increased. These effects were shown to arise from the effects of molecular crowding on the rate coefficient for propene trimer formation and were confirmed by quantum chemical analysis of the energetics of propene oligomerization. It was found that the activation for propene dimerization is unaffected by the presence of oligomers on nearby sites, but the activation energy for propene trimerization relative to desorption of hexene increases by 19kcalmol−1 when two next nearest neighbor sites are occupied by oligomers. In situ IR spectroscopy observations showed the buildup of aromatic species with time-on-stream. The accumulation of these species increases with decreasing Si/Al ratio, suggesting that increasing proximity of Brønsted-acid sites enhances the formation of aromatic species. [Copyright &y& Elsevier]

Abstract: Molecular dynamics simulations using a combined quantum mechanical and molecular mechanical (QM/MM) potential have been carried out to investigate the internal proton transfer equilibrium of the external aldimine species in l-dopa decarboxylase, and carbanion stabilization by the enzyme cofactor in the active site of alanine racemase. Solvent effects lower the free energy of the O-protonated PLP tautomer both in aqueous solution and in the active site, resulting a free energy difference of about −1kcal/mol relative to the N-protonated Schiff base in the enzyme. The external aldimine provides the dominant contribution to lowering the free energy barrier for the spontaneous decarboxylation of l-dopa in water, by a remarkable 16kcal/mol, while the enzyme l-dopa decarboxylase further lowers the barrier by 8kcal/mol. Kinetic isotope effects were also determined using a path integral free energy perturbation theory on the primary 13C and the secondary 2H substitutions. In the case of alanine racemase, if the pyridine ring is unprotonated as that in the active site, there is destabilizing contribution to the formation of the α-carbanion in the gas phase, although when the pyridine ring is protonated the contribution is stabilizing. In aqueous solution and in alanine racemase, the α-carbanion is stabilized both when the pyridine ring is protonated and unprotonated. The computational studies illustrated in this article show that combined QM/MM simulations can help provide a deeper understanding of the mechanisms of PLP-dependent enzymes. This article is part of a Special Issue entitled: Pyridoxal Phosphate Enzymology. [Copyright &y& Elsevier]

A hybrid ab initio QM/MM molecular dynamics simulation at the Hartree-Fock level has been performed to investigate structural and dynamical parameters of the V3+ ion in dilute aqueous solution. A distorted octahedral structure with the average V3+-O distance of 1.99 Å is evaluated from the QM/MM simulation, which is in good agreement with the X-ray data. Several structural parameters such as angular distribution functions, θ- and tilt-angle distributions have been determined to obtain the full description of the hydration structure of the hydrated V3+. The Jahn-Teller distortions of the V3+ ion are pronounced in the QM/MM simulation. The mean residence time of 14.5 ps is estimated for the ligand exchange processes in the second hydration shell. © 2009 Wiley Periodicals, Inc. J Comput Chem 2009 [ABSTRACT FROM AUTHOR]

Abstract: Our computer simulations of gamma glutamyl semialdehyde dehydrogenase (GGSALDH, pyrroline 5-carboxylate dehydrogenase, ALDH4) were initiated from the Thermus thermophilus crystal structures in an effort to understand the effects of a seemingly subtle mutation. In humans, a natural S352L mutation gives rise to type II hyperprolinemia (mental retardation). The mutation occurs in what might be a priori considered the outer shell of the active site, affecting a residue of no obvious significance. In another member of the superfamily (ALDH3) this serine residue is an aspartate, which tethers the “distal” Lys. It has been our hypothesis that in ALDH3 this is a beneficial interaction, enabling the “proximal” Lys to interact with the carbonyl oxygen of the peptide bond with the catalytic Cys, allowing the Cys amide N to transiently protonate the tetrahedral intermediate. That the role of this Asp is significant is proved by a natural Asp-to-Asn mutation that abolishes activity. The Ser-to-Leu exchange in GGSALDH might be expected to alter the water structure at the site of mutation, and the MM simulations clearly support this. It was our hypothesis, based on initial static models of the mutation, that the leucyl side chain would block the direct or indirect interaction of the distal Lys with the active site. Our simulations indicate that this lysine residue is indeed important in explaining the molecular pathology of the mutation. Through small rotations of its C–C bonds, the Lys ɛ-amino group comes into H-bonding distance with Ser-326, the equivalent of human Ser-352. In the S326L mutant, this interaction is not possible, while the water network from this residue to the target main-chain carbonyl oxygen is disturbed as well. [Copyright &y& Elsevier]

For decades, there has been debate regarding the origin of the catalytic power of enzymes. In this work, we use the approach of computational chemistry to study the enzyme catechol O-methyltransferase (COMT) and reveal that the two current views on the catalytic mechanism of enzymes, the rate-promoting vibrations and the electric field, may both be viewed as part of the chemical step catalyzed by COMT. However, we show that the rate-promoting vibrations cause the electrostatic effect. This work provides insight into the catalytic mechanism of COMT and resolves a longstanding controversy regarding this enzyme's mechanism., Competing Interests: The authors declare no competing financial interest.

The small GTPase Ras transmits signals in a variety of cellular signaling pathways, most prominently in cell proliferation. GTP hydrolysis in the active center of Ras acts as a prototype for many GTPases and is the key to the understanding of several diseases, including cancer. Therefore, Ras has been the focus of intense research over the last decades. A recent neutron diffraction crystal structure of Ras indicated a protonated γ-guanylyl imidodiphosphate (γ-GppNHp) group, which has put the protonation state of GTP in question. A possible protonation of GTP was not considered in previously published mechanistic studies. To determine the detailed prehydrolysis state of Ras, we calculated infrared and NMR spectra from quantum mechanics/molecular mechanics (QM/MM) simulations and compared them with those from previous studies. Furthermore, we measured infrared spectra of GTP and several GTP analogs bound to lipidated Ras on a membrane system under near-native conditions. Our findings unify results from previous studies and indicate a structural model confirming the hypothesis that γ-GTP is fully deprotonated in the prehydrolysis state of Ras., (© 2018 by The American Society for Biochemistry and Molecular Biology, Inc.)

Peptidylglycine α-hydroxylating monooxygenase is a noninteracting bicopper enzyme that stereospecifically hydroxylates the terminal glycine of small peptides for its later amidation. Neuroendocrine messengers, such as oxytocin, rely on the biological activity of this enzyme. Each catalytic turnover requires one oxygen molecule, two protons from the solvent, and two electrons. Despite this enzyme having been widely studied, a consensus on the reaction mechanism has not yet been found. Experiments and theoretical studies favor a pro-S abstraction of a hydrogen atom followed by the rebinding of an OH group. However, several hydrogen-abstracting species have been postulated; because two protons are consumed during the reaction, several protonation states are available. An electron transfer between the copper atoms could play a crucial role for the catalysis as well. This leads to six possible abstracting species. In this study, we compare them on equal footing. We perform quantum mechanics/molecular mechanics calculations, considering the glycine hydrogen abstraction. Our results suggest that the most likely mechanism is a protonation of the abstracting species before the hydrogen abstraction and another protonation as well as a reduction before OH rebinding., (© 2014 by The American Society for Biochemistry and Molecular Biology, Inc.)